tbuckley/cabot-search huggingface dataset:
Potent targeted activator of cell kill molecules eliminate cells expressing HIV-1
Authors: Carl J. Balibar, Daniel J. Klein, Beata Zamlynny, Tracy L. Diamond, Zhiyu Fang, Carol A. Cheney, Jan Kristoff, Meiqing Lu, Marina Bukhtiyarova, Yangsi Ou, Min Xu, Lei Ba, Steven S. Carroll, Abdellatif  El Marrouni, John F. Fay, Ashley Forster, Shih Lin Goh, Meigang Gu, Daniel Krosky, Daniel I. S. Rosenbloom, Payal Sheth, Deping Wang, Guoxin Wu, Matthias Zebisch, Tian Zhao, Paul Zuck, Jay Grobler, Daria J. Hazuda, Bonnie J. Howell, Antonella Converso
Journal: Science Translational Medicine (2023)

Antiretroviral therapy inhibits HIV-1 replication but is not curative due to establishment of a persistent reservoir after virus integration into the host genome. Reservoir reduction is therefore an important HIV-1 cure strategy. Some HIV-1 nonnucleoside reverse transcriptase inhibitors induce HIV-1 selective cytotoxicity in vitro but require concentrations far exceeding approved dosages. Focusing on this secondary activity, we found bifunctional compounds with HIV-1–infected cell kill potency at clinically achievable concentrations. These targeted activator of cell kill (TACK) molecules bind the reverse transcriptase–p66 domain of monomeric Gag-Pol and act as allosteric modulators to accelerate dimerization, resulting in HIV-1 + cell death through premature intracellular viral protease activation. TACK molecules retain potent antiviral activity and selectively eliminate infected CD4 + T cells isolated from people living with HIV-1, supporting an immune-independent clearance strategy.
A long-acting anti–IL-8 antibody improves inflammation and fibrosis in endometriosis
Authors: Ayako Nishimoto-Kakiuchi, Izumi Sato, Kiyotaka Nakano, Hiroshi Ohmori, Yoko Kayukawa, Hiromi Tanimura, Sachiya Yamamoto, Yuichiro Sakamoto, Genki Nakamura, Atsuhiko Maeda, Kentaro Asanuma, Atsuhiko Kato, Tadashi Sankai, Ryo Konno, Hisafumi Yamada-Okabe
Journal: Science Translational Medicine (2023)

Current pharmacological treatments for endometriosis are limited to hormonal agents that can relieve pain but cannot cure the disease. Therefore, the development of a disease-modifying drug for endometriosis is an unmet medical need. By studying human endometriotic samples, we found that the progression of endometriosis was associated with the development of inflammation and fibrosis. In addition, IL-8 expression was highly up-regulated in endometriotic tissues and closely correlated with disease progression. We created a long-acting recycling antibody against IL-8 (AMY109) and evaluated its clinical potency. Because rodents do not produce IL-8 and do not experience menstruation, we analyzed the lesions in cynomolgus monkeys that spontaneously developed endometriosis and in a surgically induced endometriosis monkey model. Both spontaneously developed and surgically induced endometriotic lesions demonstrated pathophysiology that was highly similar to that of human endometriosis. Once-a-month subcutaneous injection of AMY109 to monkeys with surgically induced endometriosis reduced the volume of nodular lesions, lowered the Revised American Society for Reproductive Medicine score as modified for monkeys, and ameliorated fibrosis and adhesions. In addition, experiments using cells derived from human endometriosis revealed that AMY109 inhibited the recruitment of neutrophils to endometriotic lesions and the production of monocyte chemoattractant protein-1 from neutrophils. Thus, AMY109 may represent a disease-modifying therapy for patients with endometriosis.
Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in <i>BRCA1 or BRCA2</i>
Authors: Priya Bhardwaj, Neil M. Iyengar, Heba Zahid, Katharine M. Carter, Dong Jun Byun, Man Ho Choi, Qi Sun, Oleksandr Savenkov, Charalambia Louka, Catherine Liu, Phoebe Piloco, Monica Acosta, Rohan Bareja, Olivier Elemento, Miguel Foronda, Lukas E. Dow, Sofya Oshchepkova, Dilip D. Giri, Michael Pollak, Xi Kathy Zhou, Benjamin D. Hopkins, Ashley M. Laughney, Melissa K. Frey, Lora Hedrick Ellenson, Monica Morrow, Jason A. Spector, Lewis C. Cantley, Kristy A. Brown
Journal: Science Translational Medicine (2023)

Obesity, defined as a body mass index (BMI) ≥ 30, is an established risk factor for breast cancer among women in the general population after menopause. Whether elevated BMI is a risk factor for women with a germline mutation in BRCA1 or BRCA2 is less clear because of inconsistent findings from epidemiological studies and a lack of mechanistic studies in this population. Here, we show that DNA damage in normal breast epithelia of women carrying a BRCA mutation is positively correlated with BMI and with biomarkers of metabolic dysfunction. In addition, RNA sequencing showed obesity-associated alterations to the breast adipose microenvironment of BRCA mutation carriers, including activation of estrogen biosynthesis, which affected neighboring breast epithelial cells. In breast tissue explants cultured from women carrying a BRCA mutation, we found that blockade of estrogen biosynthesis or estrogen receptor activity decreased DNA damage. Additional obesity-associated factors, including leptin and insulin, increased DNA damage in human BRCA heterozygous epithelial cells, and inhibiting the signaling of these factors with a leptin-neutralizing antibody or PI3K inhibitor, respectively, decreased DNA damage. Furthermore, we show that increased adiposity was associated with mammary gland DNA damage and increased penetrance of mammary tumors in Brca1 +/− mice. Overall, our results provide mechanistic evidence in support of a link between elevated BMI and breast cancer development in BRCA mutation carriers. This suggests that maintaining a lower body weight or pharmacologically targeting estrogen or metabolic dysfunction may reduce the risk of breast cancer in this population.
A phase 2 study of thalidomide for the treatment of radiation-induced blood-brain barrier injury
Authors: Jinping Cheng, Jingru Jiang, Baixuan He, Wei-Jye Lin, Yi Li, Jingjing Duan, Honghong Li, Xiaolong Huang, Jinhua Cai, Jiatian Xie, Zhan Zhang, Yuhua Yang, Yongteng Xu, Xia Hu, Minyi Wu, Xiaohuang Zhuo, Qiang Liu, Zhongshan Shi, Pei Yu, Xiaoming Rong, Xiaojing Ye, Phei Er Saw, Long-Jun Wu, Charles B. Simone, Melvin L. K. Chua, Hai-Qiang Mai, Yamei Tang
Journal: Science Translational Medicine (2023)

Radiation-induced brain injury (RIBI) is a debilitating sequela after radiotherapy to treat head and neck cancer, and 20 to 30% of patients with RIBI fail to respond to or have contraindications to the first-line treatments of bevacizumab and corticosteroids. Here, we reported a Simon's minmax two-stage, single-arm, phase 2 clinical trial (NCT03208413) to assess the efficacy of thalidomide in patients with RIBI who were unresponsive to or had contraindications to bevacizumab and corticosteroid therapies. The trial met its primary endpoint, with 27 of 58 patients enrolled showing ≥25% reduction in the volume of cerebral edema on fluid-attenuated inversion recovery-magnetic resonance imaging (FLAIR-MRI) after treatment (overall response rate, 46.6%; 95% CI, 33.3 to 60.1%). Twenty-five (43.1%) patients demonstrated a clinical improvement based on the Late Effects Normal Tissues-Subjective, Objective, Management, Analytic (LENT/SOMA) scale, and 36 (62.1%) experienced cognitive improvement based on the Montreal Cognitive Assessment (MoCA) scores. In a mouse model of RIBI, thalidomide restored the blood-brain barrier and cerebral perfusion, which were attributed to the functional rescue of pericytes secondary to elevation of platelet-derived growth factor receptor β (PDGFRβ) expression by thalidomide. Our data thus demonstrate the therapeutic potential of thalidomide for the treatment of radiation-induced cerebral vasculature impairment.
Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis
Authors: R. Camille Brewer, Tobias V. Lanz, Caryn R. Hale, Gregory D. Sepich-Poore, Cameron Martino, Austin D. Swafford, Thomas S. Carroll, Sarah Kongpachith, Lisa K. Blum, Serra E. Elliott, Nathalie E. Blachere, Salina Parveen, John Fak, Vicky Yao, Olga Troyanskaya, Mayu O. Frank, Michelle S. Bloom, Shaghayegh Jahanbani, Alejandro M. Gomez, Radhika Iyer, Nitya S. Ramadoss, Orr Sharpe, Sangeetha Chandrasekaran, Lindsay B. Kelmenson, Qian Wang, Heidi Wong, Holly L. Torres, Mark Wiesen, Dana T. Graves, Kevin D. Deane, V. Michael Holers, Rob Knight, Robert B. Darnell, William H. Robinson, Dana E. Orange
Journal: Science Translational Medicine (2023)

Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15 + HLADR hi and CD48 high S100A2 pos monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens.
Proprotein Convertase Subtilisin/Kexin Type 6: A Risk Factor for Survival in Pulmonary Fibrosis?
Authors: Ivana V. Yang
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Proprotein Convertase Subtilisin/Kexin Type 6, a Risk Factor for Survival in Pulmonary Fibrosis?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Focused Ultrasound Ablation of the Globus Pallidus Internus for Parkinson’s Disease
Authors: Anette Schrag
Journal: New England Journal of Medicine (2023)

One of the challenges in the management of advanced Parkinson's disease is the occurrence of motor fluctuations and dyskinesias in response to antiparkinsonian medications. The often unpredictable deterioration of motor function in the off-medication state and dyskinesias in the on-medication state can render patients disabled for many hours each day. Deep-brain stimulation of the subthalamic nucleus or the globus pallidus internus is an established treatment for patients with these complications.1 However, not all patients are eligible for deep-brain stimulation owing to coexisting conditions, and some are unwilling to consider this treatment because it involves invasive placement of electrodes in the . . .
Two-Year Outcomes of Valoctocogene Roxaparvovec Therapy for Hemophilia A
Authors: Johnny Mahlangu, Radoslaw Kaczmarek, Annette von Drygalski, Susan Shapiro, Sheng-Chieh Chou, Margareth C. Ozelo, Gili Kenet, Flora Peyvandi, Michael Wang, Bella Madan, Nigel S. Key, Michael Laffan, Amy L. Dunn, Jane Mason, Doris V. Quon, Emily Symington, Andrew D. Leavitt, Johannes Oldenburg, Hervé Chambost, Mark T. Reding, Kala Jayaram, Hua Yu, Reena Mahajan, Konstantia-Maria Chavele, Divya B. Reddy, Joshua Henshaw, Tara M. Robinson, Wing Yen Wong, Steven W. Pipe
Journal: New England Journal of Medicine (2023)

Valoctocogene roxaparvovec delivers a B-domain-deleted factor VIII coding sequence with an adeno-associated virus vector to prevent bleeding in persons with severe hemophilia A. The findings of a phase 3 study of the efficacy and safety of valoctocogene roxaparvovec therapy evaluated after 52 weeks in men with severe hemophilia A have been published previously.We conducted an open-label, single-group, multicenter, phase 3 trial in which 134 men with severe hemophilia A who were receiving factor VIII prophylaxis received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in the annualized rate of treated bleeding events at week 104 after receipt of the infusion. The pharmacokinetics of valoctocogene roxaparvovec were modeled to estimate the bleeding risk relative to the activity of transgene-derived factor VIII.At week 104, a total of 132 participants, including 112 with data that were prospectively collected at baseline, remained in the study. The mean annualized treated bleeding rate decreased by 84.5% from baseline (P<0.001) among the participants. From week 76 onward, the trajectory of the transgene-derived factor VIII activity showed first-order elimination kinetics; the model-estimated typical half-life of the transgene-derived factor VIII production system was 123 weeks (95% confidence interval, 84 to 232). The risk of joint bleeding was estimated among the trial participants; at a transgene-derived factor VIII level of 5 IU per deciliter measured with chromogenic assay, we expected that participants would have 1.0 episode of joint bleeding per year. At 2 years postinfusion, no new safety signals had emerged and no new serious adverse events related to treatment had occurred.The study data show the durability of factor VIII activity and bleeding reduction and the safety profile of valoctocogene roxaparvovec at least 2 years after the gene transfer. Models of the risk of joint bleeding suggest that the relationship between transgene-derived factor VIII activity and bleeding episodes is similar to that reported with the use of epidemiologic data for persons with mild-to-moderate hemophilia A. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).
Case 6-2023: A 68-Year-Old Man with Recurrent Strokes
Authors: Aneesh B. Singhal, Scott B. Silverman, Javier M. Romero, Melanie Lang-Orsini
Journal: New England Journal of Medicine (2023)

A 68-year-old man was admitted with confusion. In the past 7 weeks, imaging had shown evidence of multifocal strokes despite therapeutic anticoagulation, as well as kidney and lung masses. A diagnosis was made.
Patients with Down syndrome can be included in early phase clinical trials- a report from the T2016-003 Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) study
Authors: N. Gossai, D. Bhojwani, E. S. Schafer, B. H. Chang, L. Pommert, A. Verma, J. Malvar, Y. Y. Chi, J. Hitzler, M. J. Burke, K. R. Rabin
Journal: Leukemia (2023)
Evolving Management Practices for Early Sepsis-induced Hypoperfusion: A Narrative Review
Authors: Elizabeth S. Munroe, Robert C. Hyzy, Matthew W. Semler, Manu Shankar-Hari, Paul J. Young, Fernando G. Zampieri, Hallie C. Prescott
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Sepsis causes significant morbidity and mortality worldwide. Resuscitation is a cornerstone of management. This review covers five areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about the harms of fluid, practice is evolving toward smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60-65 mm Hg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, although it is not universally accepted. Similarly, although guidelines suggest the use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving toward fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation.
Safety and Efficacy of Denosumab for Fibrous Dysplasia of Bone
Authors: Luis F de Castro, Zachary Michel, Kristen Pan, Jocelyn Taylor, Vivian Szymczuk, Sriram Paravastu, Babak Saboury, Georgios Z Papadakis, Xiaobai Li, Kelly Milligan, Brendan Boyce, Scott M Paul, Michael T Collins, Alison M Boyce
Journal: New England Journal of Medicine (2023)
Response to Comment on Serés-Noriega et al. Use of the Steno T1 Risk Engine Identifies Preclinical Atherosclerosis Better Than Use of ESC/EASD-2019 in Adult Subjects With Type 1 Diabetes at High Risk. Diabetes Care 2022;45:2412–2421
Authors: Tonet Serés-Noriega, Laura Boswell, Verónica Perea, Antonio J. Amor
Journal: Diabetes Care (2023)
Combination of Multiple Low-Risk Lifestyle Behaviors and Incident Type 2 Diabetes: A Systematic Review and Dose-Response Meta-analysis of Prospective Cohort Studies
Authors: Tauseef A. Khan, David Field, Victoria Chen, Suleman Ahmad, Sonia Blanco Mejia, Hana Kahleová, Dario Rahelić, Jordi Salas-Salvadó, Lawrence A. Leiter, Matti Uusitupa, Cyril W.C. Kendall, John L. Sievenpiper
Journal: Diabetes Care (2023)

OBJECTIVE Combined low-risk lifestyle behaviors (LRLBs) have been associated with a reduction in type 2 diabetes risk. This relationship has not been systematically quantified. RESEARCH DESIGN AND METHODS A systematic review and meta-analysis was conducted to assess the association of combined LRLBs with type 2 diabetes. Databases were searched up to September 2022. Prospective cohort studies reporting the association between a minimum of three combined LRLBs (including healthy diet) with incident type 2 diabetes were included. Independent reviewers extracted data and assessed study quality. Risk estimates of extreme comparisons were pooled using a random-effects model. Global dose-response meta-analysis (DRM) for maximum adherence was estimated using a one-stage linear mixed model. The certainty of the evidence was assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). RESULTS Thirty cohort comparisons (n = 1,693,753) involving 75,669 incident type 2 diabetes cases were included. LRLBs, with author-defined ranges, were healthy body weight, healthy diet, regular exercise, smoking abstinence or cessation, and light alcohol consumption. LRLBs were associated with 80% lower risk of type 2 diabetes (relative risk [RR] 0.20; 95% CI 0.17–0.23), comparing the highest with lowest adherence. Global DRM for maximum adherence to all five LRLBs reached 85% protection (RR 0.15; 95% CI 0.12–0.18). The overall certainty of the evidence was graded as high. CONCLUSIONS There is a very good indication that a combination of LRLBs that includes maintaining a healthy bodyweight, healthy diet, regular exercise, smoking abstinence or cessation, and light alcohol consumption is associated with a lower risk of incident type 2 diabetes.
Aedes albopictus invasion across Africa: the time is now for cross-country collaboration and control
Authors: Joshua Longbottom, Abel W Walekhwa, Victor Mwingira, Oliver Kijanga, Furaha Mramba, Jennifer S Lord
Journal: The Lancet Global Health (2023)

The distribution of Aedes albopictus across west Africa is well documented. However, little has been done to synthesise data and establish the current distribution of this invasive vector in central and east Africa. In this Viewpoint, we show that A albopictus is establishing across Africa, how this is potentially related to urbanisation, and how establishment poses risks of near-term increases in arbovirus transmission. We then use existing species distribution maps for A albopictus and Aedes aegypti to produce consensus estimates of suitability and make these estimates accessible. Although urban development and increased trade have economic and other societal gains, the resulting potential changes in Aedes-borne virus epidemiology require a discussion of how cross-country collaboration and mitigation could be facilitated. Failure to respond to species invasion could result in increased transmission of Aedes-associated pathogens, including dengue, chikungunya, and Rift Valley fever viruses.
Readthrough compounds for nonsense mutations: bridging the translational gap
Authors: Sacha Spelier, Eveline P.M. van Doorn, Cornelis K. van der Ent, Jeffrey M. Beekman, Martijn A.J. Koppens
Journal: Trends in Molecular Medicine (2023)

Approximately 10% of all pathological mutations are nonsense mutations that are responsible for several severe genetic diseases for which no treatment regimens are currently available. The most widespread strategy for treating nonsense mutations is by enhancing ribosomal readthrough of premature termination codons (PTCs) to restore the production of the full-length protein. In the past decade several compounds with readthrough potential have been identified. However, although preclinical results on these compounds are promising, clinical studies have not yielded positive outcomes. We review preclinical and clinical research related to readthrough compounds and characterize factors that contribute to the observed translational gap.
A deep dive into degrader-induced protein-protein interfaces
Authors: Pius Galli, Carlos Pla-Prats, Nicolas H. Thomä
Journal: Trends in Pharmacological Sciences (2023)

Targeted protein degradation (TPD) relies on a comprehensive understanding of interfaces between hijacked E3 ligases and their substrates. In vitro techniques often do not capture the interaction dynamics. Recently, Hanzl et al. introduced deep mutational scanning (DMS) in combination with structural and biochemical approaches to identify residues crucial for degrader activity.
Cerium oxide nanozymes confer a cytoprotective and bio-friendly surface micro-environment to methacrylate based oro-facial prostheses
Authors: Jie Jin, Utkarsh Mangal, Ji-Young Seo, Ji-Yeong Kim, Jeong-Hyun Ryu, Young-Hee Lee, Cerjay Lugtu, Geelsu Hwang, Jung-Yul Cha, Kee-Joon Lee, Hyung-Seog Yu, Kwang-Mahn Kim, Sungil Jang, Jae-Sung Kwon, Sung-Hwan Choi
Journal: Biomaterials (2023)
Open-label study of the efficacy, safety, and durability of peanut sublingual immunotherapy in peanut-allergic children
Authors: Edwin H. Kim, Corinne A. Keet, Yamini V. Virkud, Stacy Chin, Ping Ye, Anusha Penumarti, Johanna Smeekens, Rishu Guo, Xiaohong Yue, Quefeng Li, Michael R. Kosorok, Michael D. Kulis, A. Wesley Burks
Journal: Journal of Allergy and Clinical Immunology (2023)